1. Field of the Invention
The present invention relates to novel N3S1 chelator-folate derivatives, preparation method thereof and composition for diagnosis or treatment of cancer containing the same as an active ingredient.
2. Description of the Related Art
Folate is introduced into a cell by the RFC (Reduced Folate Carrier) or folate receptor-mediated endocytosis, and generally, α-Folate receptor (α-FR) is overexpressed in a variety of cancer types such as ovarian, endometrial, breast, lung, renal, colorectal, nasopharyngeal and colon cancer, while it is present only locally in kidney or lung that stores and uses vitamins in the case of normal cells.
Folate is most frequently expressed in certain cancer type such as ovarian carcinoma and endometrial carcinoma, and is found to be expressed in more than 90% of cancer patients. Accordingly, many attempts targeting on overexpressed α-FR in cancers have been made to more effectively deliver the drug to the cancer cells and image the cancer.
α-FR is known as the membrane bound tumor-related antigen with high affinity, and it is the GPI (glycosylphosphatidylinositol) conjugated with 38 to 40 kDa membrane glycoprotein. α-FR binds with high affinity to folic acid, and the α-isoform α-FR has very low dissociation constant (Kd) with folic acid (approximately 0.1 nM), and has approximately 10 times lower dissociation constant than that of the reduced type of folates such as derivative of 5-methyltetrahydrofolate.
Meanwhile, folic acid, which is the compound having high affinity to folate receptor can maintain receptor binding property when combined by covalent bonding via γ-carboxyl group.
Recently, noninvasive imaging diagnostic agent for α-FR positive renal cell and ovarian carcinoma, which is diagnostic, radioisotope-labeled folate derivative, has successfully completed clinical phases I and II.
The noninvasive imaging method for selectively targeting tumors can accurately locate the primary lesion or tumor in the surgery, locate metastatic lesion and determine clinical stage, or observe reaction after treatment and find reoccurrence lesion.
Accordingly, it will be beneficial if it is possible to target a tumor noninvasively for the purpose of selective diagnosis or treatment, using radioisotopes.
The present inventors have been studied ways to synthesize substances to diagnose and treat α-folate receptor positive tumors in a noninvasive manner, by effectively targeting α-FR and the tumor, and were able to develop candidate substances that can effectively diagnose and treat the tumors, with positive α-folate receptor (α-FR) characteristic, by synthesizing folate derivative and introducing N3S1 chelator that can label radioisotope for diagnosis and treatment purposes, and completed the present invention.